Spectral Analysis of Guanine and Cytosine Fluctuations of Mouse Genomic DNA

We study global fluctuations of the guanine and cytosine base content (GC%) in mouse genomic DNA using spectral analyses. Power spectra S(f) of GC% fluctuations in all nineteen autosomal and two sex chromosomes are observed to have the universal functional form S(f) \sim 1/f^alpha (alpha \approx 1) over several orders of magnitude in the frequency range 10^-7< f < 10^-5 cycle/base, corresponding to long-ranging GC% correlations at distances between 100 kb and 10 Mb. S(f) for higher frequencies (f > 10^-5 cycle/base) shows a flattened power-law function with alpha < 1 across all twenty-one chromosomes. The substitution of about 38% interspersed repeats does not affect the functional form of S(f), indicating that these are not predominantly responsible for the long-ranged multi-scale GC% fluctuations in mammalian genomes. Several biological implications of the large-scale GC% fluctuation are discussed, including neutral evolutionary history by DNA duplication, chromosomal bands, spatial distribution of transcription units (genes), replication timing, and recombination hot spots.Comment: 15 pages (figures included), 2 figure

The pre treatment systemic inflammatory response is an important determinant of poor pathologic response for patients undergoing neoadjuvant therapy for rectal cancer

Background Not all patients respond equally to neoadjuvant chemoradiotherapy (nCRT), with subsequent effects on survival. The systemic inflammatory response has been shown to predict long-term outcomes in colorectal cancer. The current study examined the association between systemic inflammation and nCRT in patients with rectal cancer. Methods Between 1999 and 2010, patients who underwent nCRT were identified. Serum measurements of hemoglobin, C-reactive protein, albumin, modified Glasgow prognostic score (mGPS), and differential white cell counts were obtained before and after nCRT. The Rödel scoring system measured pathologic tumor regression, and magnetic resonance imaging and computed tomography determined radiologic staging. Results The study included 79 patients. Of these patients, 37% were radiologically downstaged, and 44% were categorized as showing a good pathologic response (Rödel scores 3 and 4). As a validated measure of the systemic inflammatory response, mGPS (P = 0.022) was associated with a poor pathologic response to nCRT. A radiologic response was associated with a good pathologic response to treatment (P = 0.003). A binary logistic regression model identified mGPS (odds ratio [OR] 0.27; 95% confidence interval [CI] 0.07–0.96; P = 0.043) and radiologic response (OR 0.43; 95% CI 0.18–0.99; P = 0.048) as strong independent predictors of a pathologic response to treatment. Conclusion The current study showed that a systemic inflammatory response before nCRT is associated with a poor pathologic response. Further study in a prospective controlled trial setting is warranted. Stephan B. Dreyer and Arfon G. M. T. Powell—contributed equally. Colorectal cancer (CRC) is the third most common cancer and the second highest cause of cancer death in the United Kingdom.1 The 5-year survival rate for CRC still is less than 60% with surgery alone, offering the only chance of cure. Rectal cancers comprise about one third of surgical resections for colorectal cancer.2 The widely adapted surgical technique of total mesorectal excision (TME), increased centralization, specialization of rectal surgery, and earlier disease detection have led to improved survival in the last 30 years.3,4 Preoperative neoadjuvant radiotherapy with or without chemotherapy currently is accepted as a standard of care for patients with margin-threatening rectal cancer. This increases disease-free survival (DFS) and sphincter preservation rates and improves circumferential resection margins and local recurrence rates.5–8 Current management of CRC in the United Kingdom involves evaluating patients using magnetic resonance imaging (MRI) and computed tomography (CT) before treatment to identify those with margin-threatening disease (T3 or T4).9 These patients are offered neoadjuvant chemoradiotherapy (nCRT) before surgical resection.10 Not all patients respond to nCRT, and there is a need to identify biomarkers of response because treatment is associated with significant morbidity. Rödel et al.11 have shown that the presence of spontaneous apoptosis in the resected specimen is a good marker of tumor regression and improved prognosis. The prognostic value of the systemic inflammatory response (SIR) has been widely studied in gastrointestinal cancers, particularly in the operative setting, using measurements of circulating markers including C-reactive protein (CRP), albumin, the modified Glasgow prognostic score (mGPS), the neutrophil lympocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and more recently, the neutrophil-platelet score (NPS) and the derived neutrophil-to-lymphocyte ratio (dNLR).12–16 This study investigated the association between markers of the systemic inflammatory response and the pathologic response to nCRT in patients with rectal cancer

Melatonin Alters Age-Related Changes in Transcription Factors and Kinase Activation

Male mice were fed 40 ppm melatonin for 2 months prior to sacrifice at age 26 months, and compared with both 26 and 4 month-old untreated controls. The nuclear translocation of NF-κB increased with age in both brain and spleen and this was reversed by melatonin only in brain. Another transcription factor, AP-1 was increased with age in the spleen and not in brain and this could be blocked by melatonin treatment. The fraction of the active relative to the inactive form of several enabling kinases was compared. The proportion of activated ERK was elevated with age in brain and spleen but this change was unresponsive to melatonin. A similar age-related increase in glial fibrillary acidic protein (GFAP) was also refractory to melatonin treatment. The cerebral melatonin M1 receptor decreased with age in brain but increased in spleen. The potentially beneficial nature of melatonin for the preservation of brain function with aging was suggested by the finding that an age-related decline in cortical synaptophysin levels was prevented by dietary melatonin

Characteristics of transposable element exonization within human and mouse

Insertion of transposed elements within mammalian genes is thought to be an important contributor to mammalian evolution and speciation. Insertion of transposed elements into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization. Elucidation of the evolutionary constraints that have shaped fixation of transposed elements within human and mouse protein coding genes and subsequent exonization is important for understanding of how the exonization process has affected transcriptome and proteome complexities. Here we show that exonization of transposed elements is biased towards the beginning of the coding sequence in both human and mouse genes. Analysis of single nucleotide polymorphisms (SNPs) revealed that exonization of transposed elements can be population-specific, implying that exonizations may enhance divergence and lead to speciation. SNP density analysis revealed differences between Alu and other transposed elements. Finally, we identified cases of primate-specific Alu elements that depend on RNA editing for their exonization. These results shed light on TE fixation and the exonization process within human and mouse genes.Comment: 11 pages, 4 figure

Using machine learning to speed up manual image annotation: application to a 3D imaging protocol for measuring single cell gene expression in the developing C. elegans embryo

<p>Abstract</p> <p>Background</p> <p>Image analysis is an essential component in many biological experiments that study gene expression, cell cycle progression, and protein localization. A protocol for tracking the expression of individual <it>C. elegans </it>genes was developed that collects image samples of a developing embryo by 3-D time lapse microscopy. In this protocol, a program called StarryNite performs the automatic recognition of fluorescently labeled cells and traces their lineage. However, due to the amount of noise present in the data and due to the challenges introduced by increasing number of cells in later stages of development, this program is not error free. In the current version, the error correction (<it>i.e</it>., editing) is performed manually using a graphical interface tool named AceTree, which is specifically developed for this task. For a single experiment, this manual annotation task takes several hours.</p> <p>Results</p> <p>In this paper, we reduce the time required to correct errors made by StarryNite. We target one of the most frequent error types (movements annotated as divisions) and train a support vector machine (SVM) classifier to decide whether a division call made by StarryNite is correct or not. We show, via cross-validation experiments on several benchmark data sets, that the SVM successfully identifies this type of error significantly. A new version of StarryNite that includes the trained SVM classifier is available at <url>http://starrynite.sourceforge.net</url>.</p> <p>Conclusions</p> <p>We demonstrate the utility of a machine learning approach to error annotation for StarryNite. In the process, we also provide some general methodologies for developing and validating a classifier with respect to a given pattern recognition task.</p

GeneWaltz--A new method for reducing the false positives of gene finding

<p>Abstract</p> <p>Background</p> <p>Identifying protein-coding regions in genomic sequences is an essential step in genome analysis. It is well known that the proportion of false positives among genes predicted by current methods is high, especially when the exons are short. These false positives are problematic because they waste time and resources of experimental studies.</p> <p>Methods</p> <p>We developed GeneWaltz, a new filtering method that reduces the risk of false positives in gene finding. GeneWaltz utilizes a codon-to-codon substitution matrix that was constructed by comparing protein-coding regions from orthologous gene pairs between mouse and human genomes. Using this matrix, a scoring scheme was developed; it assigned higher scores to coding regions and lower scores to non-coding regions. The regions with high scores were considered candidate coding regions. One-dimensional Karlin-Altschul statistics was used to test the significance of the coding regions identified by GeneWaltz.</p> <p>Results</p> <p>The proportion of false positives among genes predicted by GENSCAN and Twinscan were high, especially when the exons were short. GeneWaltz significantly reduced the ratio of false positives to all positives predicted by GENSCAN and Twinscan, especially when the exons were short.</p> <p>Conclusions</p> <p>GeneWaltz will be helpful in experimental genomic studies. GeneWaltz binaries and the matrix are available online at <url>http://en.sourceforge.jp/projects/genewaltz/</url>.</p

Lipopolysaccharide stress induces cell-type specific production of murine leukemia virus type-endogenous retroviral virions in primary lymphoid cells

Some murine-endogenous retroviruses, making up ∼10 % of the mouse genome, are induced during the course of experimental sepsis in which lipopolysaccharide (LPS), a pathogenic component of Gram-negative bacteria, often plays a critical role. In this study, we investigated whether LPS stress induces the production of murine leukemia virus type-endogenous retrovirus (MuLV-ERV) virions in primary lymphoid cells. LPS treatment of cells (single-cell suspensions and sorted B- and T-cells) isolated from seven lymphoid organs of C57BL/6J mice resulted in a differential increase in the production of MuLV-ERV virions in most cells examined. Interestingly, among the 34 unique MuLV-ERV U3 sequences cloned from the viral genomic RNAs, the nuclear respiratory factor 1 (transcription factor) element was present only in the 20 U3 sequences that were derived from the LPS-induced MuLV-ERV U3 bands. Using the U3 sequences as a probe, 55 putative MuLV-ERV loci were mapped onto the C57BL/6J mouse genome and 15 of them retained full coding potential. Furthermore, one full-length recombinant MuLV-ERV originating from a locus on chromosome 13 was determined to be responsive to LPS stress. The findings from this study suggest that LPS stress differentially activates MuLV-ERV virion production in lymphoid organs in a cell type- and MuLV-ERV-specific manner. Further investigation is needed to define the role of MuLV-ERVs in the LPS signalling pathway(s) in general, as well as in the pathogenesis of sepsis